Skip Ribbon Commands
Skip to main content
Translate
Translate
menu iconMenu
search iconSearch

Discovery of a New Signaling Mechanism May Lead to Novel Anti-Inflammatory Therapy

 

July 17, 2008  |   

A team of researchers at the University of California, San Diego School of Medicine has uncovered a new signaling mechanism used to activate protein kinases that are critical for the body’s inflammatory response.  Their work will be published in the July 18 online edition of Science (Science Express).

“In addition to helping explain the basic mechanisms of transmembrane receptor signaling, these results may identify a potential therapy for interfering with inflammation,” said Michael Karin, Ph.D., professor of pharmacology and pathology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction.

The tumor necrosis factor (TNF) receptor (TNFR) family codes for a large number of cell surface receptors of great biomedical importance, and its signaling mechanisms have been the subject of intense investigation during the past decade. Specific inhibitors of TNF receptor 1 (TNFR1) activation are being used in the treatment of rheumatoid arthritis, psoriasis and inflammatory bowel disease, and receptor activator of NF-kB (RANK) inhibitors were recently found to be effective in the treatment of osteoporosis and other bone loss diseases. 

Now Atsushi Matsuzawa, Ph.D., and Ping-Hui Tseng, Ph.D., postdoctoral fellows in the Karin laboratory, describe how engagement of CD40, a member of the TNFR family, results in assembly of multiprotein signaling complexes at the receptor.  However, according to the researchers – and  contrary to previous expectations –  signaling cascades that lead to activation of Jun Kinases (JNK) and p38 MAP Kinases (MAPK) are not initiated until these complexes dissociate from the receptor.

The authors found that complex translocation from the cell surface receptor to the cytoplasm, which is required for JNK and p38 activation, depends on degradation of a signaling protein called TRAF3.  This process can be inhibited by a class of compounds known as Smac mimics.

 “As Smac mimic compounds do not interfere with the activation of NF-kB-dependent innate immunity but do prevent the induction of JNK- and p38- dependent inflammatory mediators, they may serve as the prototypes for new anti-inflammatory therapy,” said Karin, who also noted that current drugs that work by interfering with TNFR signaling exceed $5 billion a year in revenue.           

Additional contributors include Sivakumar Vallabhapurapu, Jun-Li Luo and Weizhou Zhang, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD School of Medicine; Haopeng Wang and Dario A. A. Vignali, Department of Immunology, St. Jude Children’s Research Hospital, Memphis; and Ewen Gallagher, Department of Immunology, Imperial College, London, Faculty of Medicine, Norfolk Place, London.  Work was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, American Lung Association of California and Life Science Foundation; a Cancer Center Support CORE grant and the American Lebanese Syrian Associated Charities (ALSAC).  Karin is an American Cancer Society Research Professor.

# # #

Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu



Media Contact

Related News

4/22/2015
UC San Diego Health System and Scripps Health are partnering to provide improved continuity of patient care, fellowship training and research in hospice and palliative medicine. Under a new five-year ...
4/20/2015
Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have discovered a molecular mechanism that connects breast tissue stiffness to tumor metastasis and p ...
4/20/2015
A decrease in the amount of time spent eating and an increase in overnight fasting reduces glucose levels and may reduce the risk of breast cancer among women, report University of California, San Die ...
4/20/2015
The threat of falsified medications, also referred to as counterfeit, fraudulent, and substandard, can be quite real, yet the full scope and prevalence of the problem is poorly understood, say researc ...
4/17/2015
Researchers at the University of California, San Diego School of Medicine have created an in vitro, live-cell artificial vessel that can be used to study both the application and effects of devices us ...
4/16/2015
The increase in use of e-cigarettes has led to heated debates between opponents who question the safety of these devices and proponents who claim the battery-operated products are a useful cessation t ...
4/16/2015
An international team of scientists, led by researchers at University of California, San Diego School of Medicine, have found genetic overlap between Alzheimer’s disease (AD) and two significant cardi ...
4/13/2015
About one quarter of all atrial fibrillation patients at the lowest risk for stroke receive unnecessary blood thinners from cardiology specialists, according to a new study by researchers at Universit ...